Download topgear: a randomized phase iii trial of

TOPGEAR: the international
trial on gastro-oesophageal cancer
Could you each provide an introduction to
your respective backgrounds and explain what
drew you to your specific research fields?
RW: After graduating from the University of
Sheffield, UK, I obtained an MSc in Clinical
Epidemiology from McMaster University,
Canada. I then joined the University
of Toronto’s Department of Radiation
Oncology and was appointed Professor in
2010. My clinical research is focused on the
care of patients with gastrointestinal (GI)
malignancies, particularly those living with
metastatic and gastro-oesophageal cancer.
My goal, through well-designed research, is to
improve patient outcomes, and do so with the
least treatment-related morbidities.
CO: As a veterinarian with MSc and PhD
degrees in clinical and analytical epidemiology,
respectively, I came to the world of clinical
cancer research principally as a methodologist
with comparative medical expertise. In
my capacity as a senior investigator with
the NCIC Clinical Trials Group (CTG) with
an academic appointment as Associate
Professor in the Department of Public Health
Sciences at Queen’s University, Canada, I
provide stewardship and oversight for the
Gastrointestinal and Brain Disease Site
Committees, as well as being simultaneously
responsible for the development, execution and
analysis of several studies in partnership with
the external Clinical Study Chair.
Dr Wong, you have multiple academic
affiliations. Can you outline your
duties and explain how you manage your
time effectively?
RW: In addition to my clinical practice, which
occupies 50 per cent of my time, I have also
been given opportunities to shape initiatives
in other areas. As Director of Clinical Research
for my department, I oversee the quality and
efficiency of our clinical research programme.
At the University of Toronto’s Department of
Radiation Oncology, I serve on the executive
committee representing professionalism
and equity. As one of the co-chairs for the
Program in Evidence-Based Care, I oversee
the development of evidence-based practice
guidelines in gastrointestinal malignancies for
Ontario. As part of the faculty for the Institute
of Health Policy Management and Evaluation,
I provide formal training for graduates on
evidence-based guidelines development.
Within NCIC CTG, in addition to being co-Chair
for the gastro-oesophageal working group, I
also chair the Symptom Control Committee,
with the mandate of designing and conducting
clinical trials addressing symptoms related to
cancer and its treatments. I am still in search of
the optimal and most effective way to manage
time. Staying true to the most important goals
and not giving up perhaps keeps me on track.
On every vacation, I invariably re-evaluate and
refresh my priorities, and take up a change that
could make me work smarter!
What are your respective involvements
and designated duties in the randomised
controlled trial (RCT)?
RW: As the Canadian Principal Investigator
for the study, my role is best described as an
advocator. This involves clearly defined tasks
such as provision of methodological input to
the study, presentations at meetings, grant
writing and submission, liaising with the various
stakeholders and an anticipated strong accrual
into the trial. More critically, the role requires
effectiveness in building investigator networks
and engagement.
TOPGEAR
Drs Rebecca Wong and Chris O’Callaghan discuss their important roles in conducting an international
clinical trial to improve the outcomes for patients diagnosed with gastro-oesophageal cancer
and/or relative effectiveness in preventing
cancer or improving patient outcomes. The
NCIC CTG includes more than 80 Canadian
member institutions, including all major cancer
centres and many community hospitals, and
more than 1,200 investigators, research nurses,
data managers and pharmacists. Between its
inception in 1980 and January 2014, we have
conducted 270 trials – some of which are still
in progress – within our phase III programme
(69,585 patients) and 197 phase I or II studies
within our Investigational New Drug Program
(5,627 patients).
Conducting the trial through NCIC CTG
provides Canadian investigators with the
critical expertise needed to mount and
coordinate the Canadian portion of this trial.
Speaking broadly, what are your hopes for
the future of gastric cancer, and to what
extent will your work help contribute to
improving the outlook for patients?
RW: The future of gastric cancer needs
to involve improved prevention and early
diagnosis. Enhanced understanding of the
molecular basis of this disease along with
advances in imaging and radiotherapy delivery
may lend themselves to the development of
better prevention strategies and diagnostic
tools, as well as advances in patient selection
and choice of personalised treatment strategies.
CO: As the NCIC CTG Senior Investigator
responsible for the GI Disease Site, my role is
best described as coordinating the sponsorship
and conduct of the trial in Canada. While my
responsibilities do include methodological
input on study design and ultimately analysis
and interpretation, I will be principally involved
in the logistics and processes necessary to open
the trial at participating sites across Canada.
This trial is conducted through the NCIC
CTG, could you explain the Group’s
importance to the study?
RW: The NCIC CTG is a network of clinical
researchers whose funding includes
programmatic and project-specific peerreviewed grants. Through our funding
mechanisms, we are able to conduct national
and international clinical trials. Our mission is
to test interventions that demonstrate efficacy
WWW.RESEARCHMEDIA.EU
31
TOPGEAR
Changing protocol
As part of a wider international collaboration, a multidisciplinary team of Canadian
researchers from the NCIC Clinical Trials Group is testing the effectiveness of
preoperative chemoradiotherapy in the treatment of gastro-oesophageal cancers
ALTHOUGH GASTRIC AND oesophageal
cancers are relatively rare, they account for
a substantial proportion of cancer-related
morbidity and mortality, ranking as the 9th
and 10th national leading causes of death
respectively. In 2013, in Canada alone,
approximately 3,650 patients were diagnosed
with gastric or oesophageal cancers and around
half of these cases will be fatal. While surgery
is potentially curative in patients with local
regional disease, most patients present with
advanced disease, with a cure rate in the order
of 30 per cent.
In the search to maximise the success of gastrooesophageal resection surgery, two approaches
have been shown to improve cure rates by
approximately 10 per cent – perioperative
ECF
(epirubicin,
cisplatin,
fluorouracil)
chemotherapy, and the delivery of postoperative
chemoradiotherapy (CRT). Examining patterns of
failure provides insight into how the best aspects
of both approaches can be combined, delivering
a strategy that is optimally effective.
COMBINED TREATMENT
Incorporating radiotherapy may augment the
success of curative drugs and surgery through
improving arrest of malignant cell growth at
the site of origin. The use of a strategy that
incorporates treatment in the preoperative
setting has a number of advantages and is
expected to benefit more patients, as many are
simply not candidates for additional treatment in
the postoperative state. Radiotherapy delivered
in the preoperative setting is expected to be
more efficacious dose for dose as there is a lower
risk of hypoxia (which would limit the therapy’s
effect) at this stage. The treatment volumes
are typically smaller, resulting in less normal
tissue being irradiated and fewer side effects.
Combining these features, the use of preoperative
CRT represents a promising strategy. Indeed,
there is already evidence that suggests this
method may be effective. A meta-analysis of
four trials comparing preoperative radiotherapy
with surgery alone suggests a superior survival
rate; moreover, two phase II studies suggest
preoperative CRT to be safe and efficacious, with
significant tumour downstaging and complete
responses in the order of 30 per cent.
AN ALTERNATIVE APPROACH
Having considered the results of these clinical
trials, Canadian researchers Drs Rebecca
Wong and Chris O’Callaghan believe that the
alternative treatment strategy – the use of
preoperative CRT in addition to perioperative
32INTERNATIONAL INNOVATION
chemotherapy – will increase overall survival
of gastric and oesophageal cancer patients
undergoing surgical resection, compared to just
using perioperative chemotherapy. In a large,
international and collaborative clinical trial,
Wong and O’Callaghan are working alongside
the Australian Gastro-Intestinal Trials Group
(AGITG – Lead Investigator Dr Trevor Leong),
the European Organisation for Research and
Treatment of Cancer (EORTC – Lead Investigator
Dr Karin Hausmann), the Trans-Tasman
Radiation Oncology Group (TROG) and the
National Health and Medical Research Council
(NHMRC) Clinical Trials Centre at the University
of Sydney, on TOPGEAR: Trial Of Preoperative
therapy for Gastric and Esophagogastric
junction AdenocaRcinoma.
CANADIAN CONTRIBUTION
The Canadian facet of the trial is being
conducted by the NCIC Clinical Trials Group
(CTG). Chief Investigator Wong and Senior
Investigator O’Callaghan are overseeing the
work and anticipate around 250-375 patients
across 15 Canadian centres, out of a total
750 participants. The study concept was first
introduced to Canadian researchers in 2011,
and despite various challenges, the proposal
was prioritised by Canadian investigators as
the most important question for investigation.
“Its approval at NCIC CTG reflects the
importance of the research question, quality
of the science and strength of the investigator
networks. This is further reflected in the
successful grant application securing CAD $1.7
million from the Canadian Institutes of Health
Research,” Wong enthuses.
There are a number of reasons why preoperative
CRT is thought to have the ability to improve
patient outcomes. Primarily, the use of therapy
prior to surgery provides opportunity for tumour
downsizing, which could increase the success rate
Radiotherapy treatment plan for gastric cancer.
of the resection and reduce the chance of cancer
recurrence. Furthermore, due to the inherent
toxicity of cancer therapies, they are often better
tolerated by patients when administered before
surgery. Postoperative therapy can be disrupted
by patient morbidity so the full intended
treatment is sometimes not administered,
limiting its effect.
TRIAL OBJECTIVES
The primary objective of the trial is to determine
whether CRT prior to surgical abscission
improves patient survival compared to the sole
use of perioperative chemotherapy. Analysing
the results in more detail, the researchers will
be looking to evaluate how the addition of CRT
improves pathological response rate, surgical
cure rate and disease-free survival. Furthermore,
its effect on toxicity, quality of life and economic
perspective will also be considered.
NCIC
Clinical Trials Group
The NCIC Clinical Trials Group
(NCIC CTG) is a cancer clinical trials
cooperative group that conducts
phase I-III trials testing anti-cancer and
supportive therapies across Canada and
internationally. It is a national research
program of the Canadian Cancer
Society.
Its Central Operations and Statistics
Office is located at Queen’s
University, Kingston, Canada.
OVERCOMING HURDLES
Currently, the trial is open and recruiting
participants across Canada. It is estimated that
recruitment will be completed in around five
years’ time, with follow-up of an additional
three years to consider survivor outcomes.
Looking forward to the results of the trial, Wong
hypothesises: “I predict radiotherapy has an
important role to play in the management of
gastric cancer, and that it is more efficiently
used when applied preoperatively”. It is also
thought that although postoperative CRT has
been associated with significant toxicities,
the present trial will show that, when used
preoperatively and in combination with modern
radiotherapy techniques, it will be well tolerated
and acceptable to patients.
INTELLIGENCE
In 2013, in Canada alone, approximately 3,650 patients were
diagnosed with gastric or oesophageal cancers and around half of
these cases will be fatal
TOPGEAR
A RANDOMIZED PHASE III TRIAL OF
PREOPERATIVE CHEMORADIOTHERAPY
VS PREOPERATIVE CHEMOTHERAPY FOR
RESECTABLE GASTRIC CANCER
OBJECTIVES
From the Canadian perspective, Wong has led
the development of the study from concept
through design and into the implementation
phase. Attaining trial approval and funding
support for the required level of patient
participation has its difficulties. “Sustaining
investigator enthusiasm across the country
is probably one of the key challenges,” she
elaborates. Managing such large numbers of
scientists and clinicians from a wide variety
of disciplines requires significant network
development and engagement.
GLOBAL IMPLICATIONS
The involvement of such an internationally
diverse array of researchers and participants
has ensured the results will be widely applicable
across different nationalities. A critical feature
of the study is the pre- and post-treatment
samples that will be collected from consenting
patients. Once the data have been fully analysed
and amalgamated, the results will become part
of a highly valuable biobank, containing welldocumented clinical outcomes for different
individuals. This will be an important tool,
allowing researchers to better predict the
behaviour of gastroesophageal cancers.
The insights gained will be used to guide future
clinical trials that further probe the most
effective treatment methods for patients with
gastro-oesophageal cancer. “The improved
understanding of the predictors of response
and outcome to surgery, radiotherapy and
chemotherapy would lend itself to better patient
selection, perhaps guided by biological markers, so
that the next generation of treatment strategies
would be more effective and appropriate for
specific patients,” Wong concludes.
To test the effectiveness of using preoperative
chemoradiotherapy for the treatment of gastrooesophageal cancers.
KEY CANADIAN COLLABORATORS
NCIC Clinical Trials Group (CTG) co-investigators:
Gail Darling; Derek Jonker; Christina
Kollmansberger; Geoffrey Liu; Nicole
Mittmann; Jolie Ringash; Carol Swallow;
Dongsheng Tu; Chris O’Callaghan • TOPGEAR
Trial management committee: Trevor Leong;
Mark Smithers; Michael Michael; Alex
Boussioutas; Val Gebski; Danielle Miller
• Europe (EORTC) Chief Investigator: Karen
Haustermans • Canada (NCIC CTG) Chief
Investigator: Rebecca KS Wong
FUNDING
Canadian Cancer Society Research Institute
(CCSRI) • Canadian Institutes of Health Research
(CIHR) • National Heath and Medical Research
Council (NHMRC) • Health Research Council
(HRC) New Zealand • Cancer Society New Zealand
• Cancer Australia • EORTC Academic Fund
CONTACT
Dr Rebecca KS Wong, MBChB, MSc, FRCPC
Director, Clinical Research Program, Radiation
Medicine Program
T +1 416 946 4501
E [email protected]
Dr Chris O’Callaghan, DVM, MSc, PhD
Senior Investigator, NCIC Clinical Trials Group
Associate Professor, Department of Public
Health Sciences
T +1 613 533 6430
E [email protected]
DR REBECCA KS WONG is Professor in
Radiation Oncology at the University of Toronto,
Princess Margaret Cancer Center, University
Health Network. Her clinical interest focuses
on gastrointestinal malignancies and the use of
radiotherapy in patients living with advanced
cancers. Her research programmes can be broadly
divided into the design and implementation of
clinical trials, as well as the use of systematic
reviews and evidence-based guidelines to translate
knowledge into practice.
Canadian
Cancer Society
www.cancer.ca/en/?region=on
Over a period of more than 30
years, the NCIC CTG has applied
for and secured a Major Program
Grant from CCS, which has
provided the Group with
crucial support.
DR CHRIS O’CALLAGHAN is a veterinarian with
MSc and PhD degrees in clinical and analytical
epidemiology who came to the world of clinical
cancer research principally as a methodologist
with comparative medical expertise. In his
capacity as a senior investigator with the NCIC
CTG he provides stewardship and oversight for the
development, execution and analysis of multiple
clinical trials in gastrointestinal and central
nervous system cancers.
WWW.RESEARCHMEDIA.EU
33